Comparative Structural Crystallography and Molecular Interaction Analysis of Cholestane class of steroid derivatives

IOSR Journal of Applied Chemistry (IOSR-JAC)
e-ISSN: 2278-5736.Volume 8, Issue 12 Ver. I (Dec. 2015), PP 06-18
www.iosrjournals.org
DOI: 10.9790/5736-081210618 www.iosrjournals.org 6 |Page
Comparative Structural Crystallography and Molecular
Interaction Analysis of Cholestane class of steroid derivatives
Sonia Sharma andRajni Kant
X-ray Crystallography Laboratory, Department of Physics & Electronics, University of Jammu, India.
Abstract: Cholestane (C27H48), the parent compound of all steroids, is obtained by the removal of hydroxyl
group (from C3 position) and reduction of double bond (between C5 and C6 atoms) from the basic cholesterol
nucleus. A total number of twenty-three structures of cholestane derivatives were obtained from the CSD for a
comparative analysis of their crystallographic structures, computation of their possible biological activities and
molecular packing interaction analysis. Intermolecular interactions of the type X-H…A [X=C,O, N; A=O, Cl,
N, Br, F] have been analysed for a better understanding of molecular packing in cholestane class of steroids
and discussed on the basis of distance-angle scatter plots, with the following key questions in the background:(i)
Which of the interactions, viz. C-H…O, O-H…O, N-H…O, C-H…Cl, C-H…N, C-H…Br, C-H…F,O-H…N, are
dominant in cholestane class of steroids? (ii) Is there any preference of linearity for different hydrogen bonded
interactions? (iii) Preparing a small dedicated compendium of crystallographic data, biological activity and
hydrogen bonding interactions on a relative scale?
Keywords: Bifurcated hydrogen bond, Biological activity, Cholestane, Hydrogen bonding, Intermolecular
interactions, Steroids.
I. Introduction
Crystallographic data on steroids collected in the Atlas of Steroid Structure provide information
concerning preferred conformations, relative stabilities and substituent influence of the interactive potential of
steroid hormones. Analysis of these data indicates that observed conformational details are intra-molecularly
controlled and that the influence of crystal packing forces is not much consequential [1]. In order to revisit the
findings of this kind on a crystallography focused analysis of different classes of steroids, we got interested to
undertake independent work on various classes of steroid derivatives.
Cholesterol is convertible into a fully saturated compound, cholestane (C27H48). A representative
illustration of the cholesterol molecule is presented in Fig. 1.Without considering the detail of the reactions or
the specific compounds involved, the cholestane skeleton gives rise to some other important steroid classes as
shown in Fig.2 [2]. As a part of our research on the comparative crystallographic findings, including biological
activity predictions and molecular packing interaction analysis [3, 4 and 5], we identified a series of twenty-
three cholestane derivatives [6-24] from Cambridge Structure Database (CSD). The chemical structure of each
compound and its numbering is presented in Fig. 3 while the reference code, chemical name, chemical formula,
molecular weight and published reference is presented in Table 1.
II. Methodology
1.1 Crystallographic comparison
All the cholestane derivatives as obtained from CSD were analyzed for their precise comparative
structural parameters that include the crystal class, space group, the number of molecules per asymmetric unit
cell, the final R-factor (Table 2), selected bond distances and bond angles (Table 3). Quantitative description of
different ring conformations using asymmetry and pseudorotational parameters and available X-ray structure
data gives an impression of the conformational mobility. The ring conformations for each structure were
computed and the comprehensive data are presented in Table 4. The CIF for each structure was used as an input
to Mercury 3.5 software for the computation of possible hydrogen interactions. The geometrical restrictions
placed on the intermolecular H-bonds present in the selected pair are the sum of van der Waals radii for the
generation of quality interaction data, ignoring few very weak interactions.
1.2 Biological activity predictions
Biological activity of steroids is one of the most important reasons for their synthesis and structural
characterization. It is the result of chemical compound’s interaction with biological activity that a total matrix of
activities caused by the compound is generated which is generally referred to as the biological activity spectrum
of the substance. It is a concept that is crucial to PASS (Prediction of Activity spectra for Substances) software
which provides the rationale for predicting many activity types for different compounds[25].The structural
formula of a molecule is presented as a mol file and the predictions result is in the form of a table containing the

Comparative Structural Crystallography and Molecular Interaction Analysis of Cholestane class…
list of biological activities on a scale of probability ranging from 0-1. Two values are computed for each
activity: Pa - the probability of the compound being active and Pi - the probability of the compound being
inactive for a particular activity. Activities with Pa>Pi are retained as the most probable and predicted ones for a
given compound. The Pa and Pi values for the molecules (1-23) are presented in Table 5.
1.3 Molecular packing interaction analysis
Hydrogen bonds play a vital role in crystal engineering because of their three peculiar features i.e.,
strength, directionality and flexibility [26]. Strong hydrogen bonds such as O-H…O and N-H…O are well
documented, but weak interactions such as C-H…O , C-H…X (X-halogen atom) and C-H…N have also
attracted considerable interest because of their frequent occurrence in organic crystal structures [27, 28]. The
knowledge gained about these interactions and through their analysis help to understand the structure of
biomolecules with implications for structure-based drug design. Therefore, in the light of some latest research
going on in the field of hydrogen bonding [29,30 and 31], we examined hydrogen-bonded interactions of the
type, C-H…O, O-H…O, N-H…O, C-H…Cl, C-H…N, C-H…Br, C-H…F,O-H…N, present in cholestane
derivatives. The interaction data are presented in Table 6.
III. Results and Discussion
1.4 Comparative crystallographic analysis
Based on the crystallographic data as presented in Table 2-4, the following observations can be made:
1. The most commonly occurring crystal system is monoclinic (73.9%), followed by orthorhombic (26.1%).
The most commonly occurring space group is P21 (65.2%), followed by P212121 (26%) and C2 (8.7%).
This observation is in agreement with the findings of Stout and Jensen [32].
2. A careful analysis of reliability index (R-factor) indicates that a reasonably good level of confidence has
been achieved while reporting the crystal structure for each compound (the R-factor range being 0.0264 -
0.0920).
3. The phenomenon of multiple molecules (Zʹ=2), observed in molecules M-1, 4, 6, 8, 14, 18, 20 and 22,
respectively, is confined only to 30% of the total number of structures. Reproducible crystallization of
such a series of chemically-similar-lookingcompounds might suggest thereasons for cholestanes exhibiting
the phenomenon of multiple molecules.
4. The variation in the bond length C2-C3 (sp3
-sp3
/sp3
-sp2
/sp2
-sp3
) and C3-C4 (sp3
-sp3
/sp3
-sp2
/sp2
-sp3
) and
bond angle C2-C3-C4(sp3
/sp2
) in all the structures is quite interesting. The value of the bond C2-C3 (sp3
-
sp3
) and C3-C4(sp3
-sp3
) in all the molecules except M-6 lies in the range 1.497-1.526Å and 1.497-1.566Å,
respectively (average being 1.511Å). The bond angle C2-C3(sp3
)-C4 ranges between 108.9°- 114.39° (the
average being 111.68°). However, in M-6 [with Z'=2], both the bond distances are sp3
-sp2
/sp2
-sp3
hybridised.
5. All the three six- membered rings in twenty- three cholestane molecules adopt chair conformation, except
ring B in molecules [M-2, 14(14')] which shows sofa conformation and this may be due to the presence of
an epoxy group between C5 and C6. The relative frequency of various types of conformations occurring in
six-membered and five-membered rings in molecules (1-23) are as shown in [Fig. 4(a, b)]. The incidence
of occurrence of all the six-membered rings in chair conformation is 95.69%, followed by the sofa
conformation (4.3%). Similarly, for the five-membered ring in all the twenty-three cholestane derivatives,
the incidence of occurrence of envelope and distorted envelope conformation is 35.48%, followed by half-
chair and intermediate between half-chair & envelope conformations (35.48 & 29.03% ,respectively).
1.5 Biological activity predictions
On comparing the activities as given in the Table 5, it is quite interesting to note that most of the
cholestane derivatives possess high antieczematic, dermatologic, and antipruritic activities. The Pa > Pi indicates
that all the molecules except [M10, M-12] show high value of Choleretic activity. There appears to a quite large
probability for the molecules M-6,7,9,11,13,14,15 to exhibit anti-inflammatory activity while other molecules
are quite low on this aspect. All the molecules show high antisecretoric activity except [M-3, M-7, M-10, M-11,
M-16]. Antiseborrheic activity is predicted for almost all the molecules except [M-1, M-7, M-8, M-10, M-13,
M-20].
1.6 Molecular packing interactions
Packing interactions include both the intra and intermolecular hydrogen bonds which are directional
interactions with a preference for linear geometry [33]. These interactions can be analyzed in a better way by
making d-θ and D-θ scatter plots. The plots include all contacts found in molecule (1-23) with d <2.99Å and D
<3.86Å at any occurring angle (θ). A graphical projection of d-θ [d(H…A) against θ (X-H…A)] and D-θ

[D(X…A) against θ (X–H…A)] scatter plots is presented in Fig.5(a,b). The following inference can be drawn
from the d-θ and D-θ scatter plots:
(i) The scatter spots in the C-H…O hydrogen bond clusters lie in the range of d(H…A) = 2.30-2.72;
D(X…A) = 3.3-3.55 and θ (X–H…A) = 130-170°, respectively.
(ii) The density of spots for the O-H…O type of hydrogen bond is maximum [range for d (H…A) =1.8-2.0
Å, D(X…A) =2.6-2.8 Å, θ(X–H…A)=165°-178°]. Most of the O-H…O contacts belongs to the category
of strong H-bonds whereas C-H…O contacts falls in the range of weak interactions.
(iii) The relative frequency of occurrence of various types of C-H...O, O-H...O, N-H…O, C-H…Cl, C-H…N,
C-H…Br, C-H...F and O-H…N intermolecular hydrogen bonds is 48.61, 27.77, 4.16, 4.166, 1.38, 6.94,
1.38 and 5.55%, respectively and is presented in Fig.6,thus making C-H…Oas the most preferred
intermolecular interaction in cholestane class of steroids.
(iv) For the overall description of all the intermolecular hydrogen interactions of the type C-H...O, O-H...O,
N-H…O, C-H…Cl, C-H…N, C-H…Br, C-H...F and O-H…N,the minimum and maximum values for
distance (d and D) and angle (θ) are d(H…A)= 1.73-3.01Å, D=2.45-3.86Å and θ(X–H…A)= 124.2-
179.8°, respectively.
(v) The values for the dominant C-H…O and O-H…O hydrogen bonds (Table 7), when compared with
the data as reported by Desiraju and Steiner [34], provided us a way for the classification of hydrogen
bonding present in cholestane derivatives. The overall D(X-A) and d(H…A) range as obtained in case of
C-H…O hydrogen bonds is between 2.45-3.68Å and 2.31-2.71Å, respectively; thus making these
interactions fall under the category of “very strong to weak” while the θ(X–H…A) range (119.9-169.2⁰)
suggests these interactions to be weak. However, in case of O-H…O hydrogen bonds, the D(X-A) and
d(H…A) range lies between 2.57-3.62Å and 1.73-2.64Å, respectively, indicating these interactions to be
“strong to weak” , while the θ(X–H…A) range (129.4-179.4⁰) in case of O-H…O hydrogen bonds
suggests the presence of O-H…O as strong interactions.
Bifurcated hydrogen bonds are observed in O-H…O and N-H…O hydrogen bonded structures [35].
They are also observed in C-H…O/N patterns. In the present study, few bifurcated hydrogen bonds of the type
C-H…O and O-H…O have also been observed, besides the presence of a trifurcated hydrogen bond in M-16. In
molecule M-1, the asymmetric unit has two independent molecules. Oxygen atom O1and O1' act as a bifurcated
hydrogen bond donor forming intermolecular bonds [O1-H1A…N1'and O1-H1A…O1 O1-H1'; O1'-H1B…N1
and O1'-H1B…O1] with bifurcated angle of 292.9° and 279.8°.Oxygen atom O6 of M-3 acts as bifurcated
acceptor with bifurcated angle of 314.5° forming [C26-H261…O6 and C1-H2…O6] hydrogen bonds. In M-
2(the asymmetric unit having two independent molecules), the oxygen atom O2 of the ketone group acts as a
bifurcated acceptor, forming two hydrogen bonds [C17'-H11L…O2 and C19'-H11R…O2], having bifurcated
angle of 279.1°. In molecules M-11,14,16, 21,22, the oxygen atoms O4, O1',O3,O2, O6, O1 and O1' act as
bifurcated acceptor forming hydrogen bonds [C2-H4…O4 andO1-H46…O4; C4-H4A…O1' and O1-H1…O1';
C6-H6…O3 and O1-H1…O3,O3-H3…O2 and C1-H1B…O2; C6-H6…O6 and O5-H5A…O6; C1-H7AA…O1
and C23'-H23D…O1,C23-H23B…O1' and C1'-H7BA…O1'].In molecule M-20, having two
crystallographically independent molecules in the asymmetric unit, the oxygen atoms O1and O1' are involved in
bifurcated hydrogen bonding [H1-atom of O1is shared between O1-N2 and O1-O1'], forming two
intermolecular H-bonds[O1-H1…N2,O1-H1…O1'] with bifurcated angle of 282.9°and H4-atom of O1' is shared
between O1'-N1 and O1'-O1, forming two intermolecular H-bonds[O1'-H4…N1,O1'-H4…O1] with an
bifurcated angle of 288.2°, respectively. The oxygen atom O1 acts as a bifurcated acceptor in O1'-H4…O1and
C3-H4A…O1 hydrogen bonds, the bifurcated angle being 286.9°. A representative view of bifurcated hydrogen
bond formation is shown in Fig. 7.
IV. Figures and Tables
Figure1.The cyclopentanoperhydrophenanthrene nucleus and the numbering scheme of cholesterol.

Cholestane (C27)
I II III IV
Cholane (C24) Pregnane (C21) Androstane (C19) Estrane (C18)
Figure2.Relationship between various parent steroid hydrocarbon and cholestane.

Figure3.Chemical structures of molecules (1-23).
(a)
(b)
Figure4. (a) Relative frequency of occurrence (in %)for various types of conformations in six-memberedrings
A, B and C(molecules 1-23).
(b) Relative frequency ofoccurrence (in %) for various types ofconformations in five- membered
ringsD(molecules 1-23).

Figure5. (a) d-θ scatter plot for intermolecular C-H...O, O-H...O, N-H...O, C-H...Cl, C-H...N C-
H...Br and C-H…F.
(b) D-θ scatter plot for intermolecular C-H...O, O-H...O, N-H...O, C-H...Cl, C-H...N,
C-H...Br and C-H…F.
100
120
140
160
180
200
2 2.3 2.6 2.9 3.2 3.5 3.8 4.1
C-H...O
O-H...O
N-H…O
C-H...Cl
C-H…N
C-H…Br
C-H…F
O-H…N
X-A (D)
X-H...A(θ)

Figure6.Relative frequency of occurence (in %) for various types of intermolecularhydrogen bonding.
Figure7.Representative view of bifurcated hydrogen bonding in molecule M-11.
Table1. CSD code, chemical name, chemical formula, molecular wt. and reference of Molecule 1-23
Molecule CSD Code Chemical Name Chemical
Formula
Molecular
Weight
(amu)
Reference
M-1 CEHHAA 6-Hydroxyimino-5-cholestane C27H47NO 401.65 6
M-2 ESIKOG 5,6-Epoxy-3-cholestanyl acetate C29H48O3 444.67 7
M-3 GUXJUE Triacetoxy-22-iodo-24-ethyl-5-cholestan-6-one C35H55IO7 714.69 8
M-4 HUNBAT 3-Acetoxy-5-cholestan-6-one semicarbazone C30H51N3O3 501.00 9
M-5 HUXHEO (3R,5R,6R,8S,9S,10R,13R,14S,17R,20R)-6-
chloro-5-hydroxy-3- Methoxycholestane
C28H49ClO2 453.12 10
M-6 IDIKUB (5,7)-7-Hydroxy-4,4,7-trimethylcholestan-3-
one
C30H52O2 444.72 11
M-7 MIVHOP 4-(5-Dimethyl-1,3-dioxan-2-yl)-5-H-
cholestane
C33H58O2 486.79 12
M-8 NENREE 4-Methyl-5-cholestan-3-yl 4-bromobenzoate C35H53BrO2 585.68 13
M-9 PIDTAY 5,6-Dihydroxycholestan-3-yl acetate C29H50O4 462.69 14
M-10 POQTAR anti-3,5-Diacetoxy-6-nitroiminocholestane C31H50N2O6 546.73 15
M-11 RAWHIG (22R,23R,24S)-3,22,23-Trihydroxy-24-
(trifluoromethyl)-5-cholestan-6-one methanol
solvate
C28H45F3O4,CH4O 470.0 16
M-12 SEBPAR 5,6-Dibromo-3-chlorocholestane C27H45Br2Cl 564.90 17
M-13 SEBPEV 5-Bromo-3-chloro-6-methoxycholestane C28H48BrClO 516.02 17
M-14 SEDWOP 5,6-Epoxycholestan-3-ol methanol solvate C27H46O2,0.5(CH4O) 418.66 18
M-15 SEDWUV 5,6-Epoxycholestan-3-ol methanol solvate C27H46O2,CH4O 434.68 18
M-16 SEDXAC 5-Hydroxy-6-(2- C29H52O3S 480.77 18

hydroxyethylsulfanyl)cholestan-3-ol
M-17 SELZAL (25R)-26-Iodo-3-acetoxy-5-cholestane-16,22-
dione
C29H45IO4 584.55 19
M-18 SELZEP (25R)-26-Iodo-3-acetoxy-5-cholestane-
11,16,22-trione
C29H43IO5 598.53 19
M-19 SUQDUE 4-Bromo-5-cholestan-3-ol C27H47BrO 467.56 20
M-20 UNOZIH 3-Acetoxy-6-hydroxyiminocholestane C29H49NO3 459.69 21
M-21 VOJBIG 6-Acetamido-5-hydroxycholestan-3-yl acetate C31H53NO4 503.74 22
M-22 YAXYAZ 3-Chloro-5-cholestan-6-one C27H45ClO 421.08 23
M-23 ZZZQLQ01 3,3-Dibromocholestane C27H46Br2 530.46 24
Table2. Preliminary crystal data for Molecule 1-23
Molecule Crystal system Space group R-factor Z(Z′)
M-1 Monoclinic P21 0.0494 4(2)
M-2 Monoclinic P21 0.0759 2
M-3 Monoclinic C2 0.0397 4
M-4 Orthorhombic P212121 0.05 8(2)
M-5 Orthorhombic P212121 0.0378 4
M-14 Monoclinic P21 0.0628 4(2)
M-18 Monoclinic P21 0.0920 4(2)
M-21 Monoclinic C2 0.0496 4
M-22 Monoclinic P21 0.0666 4(2)
Table3. Selected bond distances (Å) and bond angles (°) for molecules (1-23)
Molecule Bond Distance(Å)
[C 2 - C3]
Bond Distance(Å)
[C 3 - C4]
Bond Angle(°)
sp3
-sp3
sp3
-sp2
/
sp2
-sp3
sp3
- sp3
sp3
- sp2
/
sp2
- sp3
C3(sp3
) C3(sp2
)
M-1 1.511 1.52 110.62
M-1' 1.526 1.522 110.86
M-2 1.521 1.566 109.77
M-3 1.494 1.54 108.99
M-4 1.498 1.509 111.25
M-4' 1.519 1.512 112.13
M-5 1.519 1.533 111.59
M-6 1.497 1.52 115.99
M-6' 1.493 1.52 116.72
M-7 1.518 1.534 111.82
M-8 1.502 1.527 112.45
M- 8' 1.495 1.514 112.84
M-9 1.512 1.498 112.76
M-10 1.518 1.519 111.78
M-11 1.52 1.522 112.59

M-12 1.514 1.517 112.96
M-13 1.503 1.52 112.74
M-14 1.521 1.509 110.89
M- 14' 1.506 1.537 111.32
M-15 1.51 1.514 109.9
M-16 1.523 1.518 110.87
M-17 1.495 1.499 112.98
M-18 1.495 1.545 109.31
M-18' 1.53 1.497 114.39
M-19 1.509 1.518 110.98
M-20 1.512 1.511 111.97
M-20' 1.51 1.514 111.82
M-21 1.511 1.512 111.74
M-22 1.515 1.523 112.27
M- 22' 1.525 1.507 112.2
M-23 1.491 1.521 113.04
Table4.Different types of conformations in the individual ring systems for Molecule 1-23
Molecule Ring A
(conformation)
Ring B
(conformation)
Ring C
(conformation)
Ring D
(conformation)
M-1 Chair Chair Chair Envelope
M-1' Chair Chair Chair Envelope
M-2 Chair Sofa Chair Intermediate between
envelope and half-chair
M-4 Chair Chair Chair Distorted envelope
M-4' Chair Chair Chair Half-chair
M-5 Chair Chair Chair Intermediate between
M-6 Chair Chair Chair Half-chair
M-6' Chair Chair Chair Intermediate between
M-14 Chair Sofa Chair Intermediate between
M-14' Chair Sofa Chair Intermediate between
M-15 Chair Sofa Chair Half-chair
M-20' Chair Chair Chair Half-chair
M-22' Chair Chair Chair Intermediate between
Table5. Pa and Pi values for the Molecule 1-23
Molecule Dermatologic
Pa> Pi
Antiinflam
matory
Pa> Pi
Antiseborrheic
Pa> Pi
Antisecretoric
Pa> Pi
Antieczematic
Pa> Pi
Choleretic
Pa> Pi
Antipruritic
Pa> Pi
M-1 0.731 >0.006 - 0.296 >0.125 - 0.777 >0.024 - 0.623 >0.013

M-2 0.673 >0.009 0.282 >0.108 0.540 >0.065 0.776 >0.005 0.785 >0.022 0.408 >0.017 0.782 >0.004
M-3 0.674 >0.009 0.379 >0.015 0.485 >0.075 0.264 >0.109 - - 0.535 >0.027
M-4 0.655 >0.011 0.251 >0.211 - - 0.725 >0.037 0.370 >0.021 0.716 >0.007
M-5 0.639 >0.012 0.323 >0.141 0.390 >0.095 - 0.781 >0.023 0.448 >0.013 0.777 >0.004
M-6 0.728 >0.006 0.500 >0.057 0.352 >0.106 0.375 >0.065 0.779 >0.023 0.936 >0.001 0.705 >0.008
M-7 0.782 >0.005 0.544 >0.045 0.221 >0.167 0.244 >0.125 0.803 >0.018 0.644 >0.005 0.734 >0.006
M-8 0.676 >0.009 0.386 >0.103 0.230 >0.160 0.498 >0.030 0.801 >0.018 0.549 >0.007 0.600 >0.016
M-9 0.698 >0.008 0.493 >0.059 0.496 >0.073 0.496 >0.073 0.840 >0.011 0.697 >0.004 0.789 >0.004
M-10 0.683 >0.009 0.289 >0.171 0.194 >0.190 0.195 >0.172 0.803 >0.018 0.254 >0.050 0.612 >0.014
M-11 0.712 >0.007 0.677 >0.019 0.606 >0.054 0.273 >0.104 0.786 >0.022 0.779 >0.003 0.654 >0.011
M-12 0.650 >0.011 - - - 0.665 >0.058 0.174 >0.100 0.559 >0.022
M-13 0.694 >0.008 0.466 >0.067 0.237 >0.155 - 0.779 >0.023 0.395 >0.018 0.783 >0.004
M-14 0.704 >0.008 0.430 >0.081 0.432 >0.086 0.680 >0.011 0.810 >0.017 0.644 >0.005 0.790 >0.004
M-15 0.704 >0.008 0.430 >0.081 0.432 >0.086 0.680 >0.011 0.810 >0.017 0.644 >0.005 0.790 >0.004
M-16 0.671 >0.010 0.373 >0.110 0.356>0.104 0.249 >0.121 0.747 >0.031 0.611 >0.005 0.682 >0.009
M-17 0.673 >0.009 - 0.763 >0.026 0.433 >0.047 0.753 >0.030 0.713 >0.004 0.674 >0.009
M-18 0.602 >0.015 - 0.721 >0.034 0.378 >0.065 0.681 >0.052 0.748 >0.003 0.636 >0.012
M-19 0.712 >0.007 - 0.473 >0.077 0.346 >0.074 0.817 >0.015 0.688 >0.004 0.700 >0.008
M-20 0.722 >0.007 0.282 >0.179 0.284 >0.130 - 0.773 >0.024 0.614 >0.005 0.704 >0.008
M-21 0.626 >0.013 - - - 0.734 >0.006 0.479 >0.010 0.734 >0.006
M-22 0.765 >0.005 - 0.381 >0.098 - 0.743 >0.032 0.523 >0.008 0.797 >0.004
M-23 0.746 >0.005 - 0.606 >0.054 0.426 >0.049 0.813 >0.016 0.680 >0.004 0.715 >0.007
Table6. Geometry of C-H...O, O-H...O, N-H…O, C-H…Cl, C-H…N, C-H...Br, C-H…F and O-H…N
Intermolecularinteractions.
Molecule
[Number of
Donors and
Acceptors]
Intermolecular
interactions
X-H...A
H...A(Å)
d
X...A(Å)
D
X-H...A(°)
θ
M-1
CEHHAA
Donors=2
Acceptors =4
O1-H1A…N1'
O1'-H1B…N1
O1-H1A…O1'
O1'-H1B…O1
1.938
1.980
2.608
2.647
2.779
2.790
3.249
3.249
161.7
154.9
131.2
124.9
M-2
ESIKOG
Donors=1
Acceptors =1
C32-H323…O3 2.707 3.577 151
M-3
GUXJUE
Donors=3
Acceptors =2
C26-H261…O6
C1-H12…O6
C2-H2…O32
2.712
2.533
2.650
3.564
3.482
3.291
148.1
166.4
123.3
M-4
HUNBAT
Donors=3
Acceptors =3
N2-H1...O3'
N3-H3A...O2
N2'-H2'A...O3
1.936
2.101
2.046
2.869
2.931
2.835
174.2
161.8
153.5
M-5
HUXHEO
Donors=2
Acceptors =2
O1-H1…O2
C17-H17…Cl
1.995
2.750
2.827
3.689
170.6
156.6
M-6
IDIKUB
Donors=2
Acceptors =2
O7'-H57D…O3
O7-H7D…O3'
2.140
2.062
2.949
2.883
170.6
176.2
M-7
MIVHOP
Donors=1
Acceptors =1
C4F-H4F1…O2 2.594 3.536 167
M-8
NENREE
Donors=3
C26-H26A…Br1
C17'-H11L…O2
C19'-H11R…O2
2.999
2.699
2.648
3.679
3.526
3.447
127.4
140.3
138.8

Acceptors =2
M-9
PIDTAY
Donors=1
Acceptors =1
O3-H31…O4 2.053 2.85 164
M-10
POQTAR
Donors=4
Acceptors =4
C29-H29C…O30
C23-H23B…O28
C16-H16B…O7
C18-H18C…N1
2.314
2.615
2.588
2.699
3.233
3.478
3.376
3.531
160.0
148.2
138.4
145.3
M-11
RAWHIG
Donors=6
Acceptors =6
O5-H49…O1
O4-H48…O5
C1-H1…O2
C7-H9…O3
C2-H4…O4
O1-H46…O4
C2-H3…F2
1.737
1.959
2.426
2.647
2.695
2.255
2.589
2.763
2.741
3.393
3.344
3.685
3.217
3.620
171.9
129.9
145.7
119.9
139.9
179.8
153.3
M-12
SEBPAR
Donors=2
Acceptors =2
C21-H21A…Cl1
C1-H1A…Br1
2.937
2.927
3.812
3.802
150.6
149.1
M-13
SEBPEV
Donors=2
Acceptors =2
C23-H3…O1
C15-H15B…Br1
2.659
2.978
3.598
3.867
158.4
151.3
M-14
SEDWOP
Donors=4
Acceptors =3
O5-H5…O1
O1'-H3…O5
C4-H4A…O1'
O1-H1…O1'
1.854
1.870
2.702
1.904
2.650
2.705
3.419
2.733
152.6
172.2
129.5
168.5
M-15
SEDWUV
Donors=3
Acceptors =3
O3-H3A…O1
C7-H7B…O2
O1-H1…O3
1.792
2.537
1.833
2.577
3.464
2.662
154.8
155.8
169.0
M-16
SEDXAC
Donors=6
Acceptors =3
C6-H6…O3
O1-H1…O3
O3-H3…O2
C1-H1B…O2
O2-H2…O1
C3-H3B…O2
2.673
1.891
1.837
2.713
1.961
2.626
3.389
2.723
2.678
3.574
2.789
3.529
128.7
170.5
179.4
145.6
168.5
149.1
M-17
SELZAL
Donors=1
Acceptors =1
C27-H27A…O1 2.446 3.405 169.1
M-18
SELZEP
Donors=6
Acceptors =6
C29-H29…O4'
C29'-H58C…O5
C15-H15B…O3'
C18-H18A…O2
C8'-H37…O1
C27-H27A…O5'
2.623
2.717
2.528
2.705
2.634
2.589
3.517
3.376
3.345
3.483
3.406
3.495
155.1
126.4
141.8
138.6
135.6
155.6
M-19
SUQDUE
Donors=1
Acceptors =1
C2-H2A…Br 2.998 3.994 160.4
M-20
UNOZIH
Donors=5
Acceptors =6
O1'-H4…N1
O1'-H4…O1
O1-H1…N2
O1-H1…O1'
C29-H9C…O3'
C29'-H37C…O3
C3-H4A…O1
1.821
2.571
1.877
2.570
2.580
2.404
2.604
2.733
3.243
2.810
3.243
3.404
3.373
3.556
160.2
128.0
157.3
125.6
141.7
169.2
158.9
M-21
VOJBIG
Donors=3
Acceptors =2
C6BH6BA…O3B
C6-H6…O6
O5-H5A…O6
2.620
2.588
1.989
3.257
3.385
2.804
124.2
138.5
172.3
M-22
YAXYAZ
Donors=5
Acceptors =3
C1-H7AA…O1
C23'-H23D…O1
C23-H23B…O1'
C1'-H7BA…O1'
C26-H26E…Cl1'
2.374
2.502
2.507
2.471
2.917
3.349
2.453
3.414
3.265
3.624
168.2
160.9
152.2
136.8
129.9
M-23
ZZZQLQ01
Donors=1
C6-H6A…Br2 3.015 3.74 136.1

Acceptors =1
' indicates second crystallographically independent molecule;
Table7. Geometrical parameters for very strong, strong and weak hydrogen bonds
Property Very strong Strong Weak Present work
C-H…O O-H…O
D(X-A)
range (Å)
2.0 -2.5 2.5 - 3.2 3.0 - 4.0 2.45-3.68 2.57-3.62
d(H…A)
range (Å)
1.2 -1.5 1.5 - 2.2 2. 0 - 3.0 2.31-2.71 1.73- 2.64
θ(X-H…A)
range(⁰)
175 - 180 130 -180 90 - 180 119.9- 169.2 124.9- 179.4
V. Conclusion
1. The cholestane class of steroids have been analysed in the present work for their crystallographic
comparison, biological activity predictions and molecular packing interactions.
2. Some general but useful inferences have been drawn about the crystal structures of the identified series of
cholestane derivatives.
3. The biological activity predictions have been made on the basis of a probability scale (Pa and Pi) generated
through PASS software.
4. The nature of the substituent at C3 position of the cholestane nucleus makes these molecules very
interesting candidates for hydrogen bonding analysis. In most of the cases, the substituent at C3 position is
primarily responsible for the occurrence of intermolecular hydrogen bonding in cholestanes. These
substitutions are linked by intermolecular hydrogen bonding which in turn help to understand the
dynamics of stacking interactions in supramolecular structures.
5. A careful examination of the entire interaction data reveals that the C-H…O hydrogen bonding is quite
predominant in cholestane derivatives. Almost all the O-H…O contacts belongs to the category of strong
hydrogen bonds while majority of C-H…O contacts belongs to weak interactions.
6. A small compendium containing information about the comparative crystallography, biological activity
prediction and detailed hydrogen bonding analysis of cholestane derivatives is thus presented in the form
of this report. It is expected that these findings shall form the basis for the contemplation of further work
on different classes of steroid derivatives.
Acknowledgements
One of the authors, Rajni Kant is thankful to the Indian council of Medical Research, New Delhi for
research funding under project grant no: BIC/12(14)2012.
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